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Wang et al. Genotoxic NF-kB activation in cancer

Nuclear steps: ATM phosphorylates SUMOylated to sites of SSB and DSB as a DNA damage sensor.
NEMO After recruitment to the breaks, PARP-1 is activated
ATM is the pivotal kinase involved in NF-kB activation by post-translational modifications by adding poly
following DNA damage. In 1998, Lee et al. first (ADP-ribose) to acceptor proteins such as itself and
[55]
observed that NF-kB activation by IR was reduced histones. PARylation alters the steric properties of
in human cells with ATM deficiency (A-T cells). Later the PARylated proteins, leading to change of their
Piret et al. reported that decreased NF-kB activation interacting partners. PARP-1 is essential for maintaining
[56]
by the chemotherapeutic drug CPT in A-T cells could genomic integrity and involved in base excision repair,
be restored by complementation with ATM. Moreover, SSB and DSB repair, DNA methylation, transcription

both IR and NCS treatment induced ATM-dependent regulation, and also signal transduction. [61-63] DNA-
IKKβ activation in HEK293 cells. Therefore, the bound PARylated PARP-1, or free PARylated PARP-
[46]
activation of ATM by DNA damage likely serves as a 1 in the nucleoplasm, serves as a docking platform
cornerstone to bridge nuclear DNA damage response for several proteins, such as PIASy. [64,65] Upon DNA
to cytoplasmic activation of NF-kB signaling cascade. damage, PARylated PARP-1 was found to form a
transient nuclear signalsome along with ATM, NEMO
The IKK kinase complex is the core component of the and PIASy, and PIASy binding to active PARylated
classical NF-kB cascade which is also required for DNA PARP1 is essential for DNA damage-induced NEMO
damage induced NF-kB activation. The non-catalytic SUMOylation and nuclear accumulation. A recent
[65]
subunit of the IKK complex, NEMO, was found to play study also identified Src-associated-substrate-during-
unique roles in mediating genotoxic NF-kB activation mitosis-of-68 kDa/KH domain containing RNA binding,
which may be dispensable in classical NF-kB signaling. signal transduction-associated 1 (Sam68/KHDRBS1)
For example, the C-terminal zinc finger (ZF) domain of as a key NF-kB regulator in the genotoxic stress-
[66]
NEMO was shown to be essential for NF-kB activation initiated NF-kB signaling pathway. Sam68 deficiency
following treatment with DNA-damaging agents. In abolished DNA damage-induced PARylation and the
contrast, NEMO ZF domain deletion minimally affected PARP1-dependent NF-kB-mediated transactivation
NF-kB activation following treatment with canonical of anti-apoptotic genes. Consistently, Sam68 deficient
stimuli (e.g. lipopolysaccharide). Importantly, a small cells are hypersensitive to genotoxic treatment while
fraction of NEMO was found to disassociate from overexpression of Sam68 elevated PAR production
IKKα/β upon DNA damage and translocate into nucleus and NF-kB-mediated anti-apoptotic transcription in
by association with IPO3 (importin 3, transportin 2). colon cancer cells. Another study suggested that cell
[57]
Subsequently, nuclear NEMO can be modified by a membrane protein MUC13 may also participate in
small protein called SUMO (small ubiquitin-like modifier) regulation of genotoxic NF-kB signaling. Although
in the nucleus in response to DNA damage. Similar the detailed mechanism is still unclear, it may involve
[58]
to ubiquitin, SUMO can be covalently conjugated onto stabilization of PARP1, enhanced ATM phosphorylation
lysine residue of its target proteins and thereby altering and NEMO SUMOylation. [67]
the function and activity of the SUMOylated proteins.
SUMO E3 ligase PIASy (protein inhibitor of activated In cells exposed to genotoxic treatments, increased
STATy)-mediated SUMOylation on K277 and 309 of nuclear localization of NEMO substantially enhances
[68]
NEMO enhanced its nuclear accumulation which is its association with ATM. Furthermore, PARP-1
essential for subsequent signaling events activating may also stabilize the interaction between NEMO
NF-kB upon DNA damage. [58,59] Nevertheless, the and ATM through PARylation of ATM and formation
mechanism through which SUMOylated NEMO is of the aforementioned nuclear signalsome. The
[65]
localized to nucleus is still unclear. association between NEMO and activated ATM leads
to ATM-dependent phosphorylation of NEMO on Ser
Two different protein complexes have been shown to 85. The precise function of NEMO phosphorylation
[68]
regulate the NEMO SUMOylation. Subsequent to DNA remains to be determined, but ATM activity and intact
damage, p53-induced death domain protein (PIDD) NEMO-Ser85 are prerequistites for subsequent
and receptor interacting protein 1 (RIP1) associate with NEMO monoubiquitination, suggesting NEMO
nuclear NEMO as a heterotrimer and accumulate in the phosphorylation on Ser85 may serve as a cue for its
nucleus. This PIDD/RIP1/NEMO complex may promote subsequent ubiquitination, such as cIAP1 recruitment.
NEMO SUMOylation following chemotherapeutic drug E3 ubiquitin ligase cIAP1, was shown to mediate
treatment in HEK293 cells. The second modulator of NEMO mono-ubiquitination at K277 and 309 in the
[60]
NEMO SUMOylation is poly (ADP-ribose) polymerase nucleus upon DNA damage in an ATM-dependent
1 (PARP-1). PARP-1 is an abundant chromatin- manner. cIAP1 may compete with SUMO ligase
[69]
associated enzyme that can be quickly recruited PIASy for NEMO association, as both bind to the same
Journal of Cancer Metastasis and Treatment ¦ Volume 3 ¦ March 27, 2017 49